Background Standard of care after surgery for high-grade gliomas (HGG), including glioblastoma (GBM) and anaplastic astrocytoma, is radiation therapy (RT) and temozolomide (TMZ). Unfortunately, lymphopenia commonly occurs after treatment, leading to decreased survival.^1,2 Concentrations of interleukin-7 (IL-7), a T-cell homeostatic cytokine, are inappropriately low in patients with HGG.³ Our previous work, using murine glioma models, demonstrated that NT-I7 (efineptakin alfa), a long-acting recombinant human IL-7, corrects lymphopenia and improves survival.⁴ Here we examine survival, safety, and change in absolute lymphocyte counts (ALCs) following administration of NT-I7 after concurrent RT/TMZ in patients with newly diagnosed HGG.

Methods Key inclusion criteria for this Phase I/II study included ALC ≥ 600 cells/mm³. NT-I7 was administered intramuscularly within 2 weeks after completion of concurrent RT/TMZ and then every 12 weeks for up to 4 doses. The primary objective of the Phase I portion was to determine safety and the maximum tolerated dose (MTD) of NT-I7 using a 2-dose accelerated phase, followed by a 3+3 design. The Phase II portion (ongoing) is a double-blind, randomized study of 20 HGG patients (10 per arm) to compare ALC changes after administration of either NT-I7 at the MTD or placebo. Exploratory objectives include immune profiling and survival analysis.

Results Phase I completed accrual with results as follows: 19 patients enrolled (17 GBM, median age 58.0 years [25-78], median baseline ALC 1000 cells/mm³ [400-2,000], median baseline dexamethasone use 0 mg/day [0-12], cut-off date 7/15/22). Twelve patients (63%) were MGMT promotor unmethylated, as unmethylation is associated with worse survival. The median number of NT-I7 doses administered was 2 [2-4]. NT-I7 was well-tolerated with grade 1/2 injection site reactions (42%) the most common treatment-related adverse event (TRAE). The MTD was 720 mcg/kg due to two grade 3 dose-limiting toxicities at 960 mcg/kg (elevated alanine aminotransferase and back pain). Dose-dependent increases in ALC were observed at 4 weeks (1.3-4.1 times of baseline level), persisting up to 12 weeks. Median progression-free survival (mPFS) was 19.1 months (95%CI: 15.1-NA) and median overall survival (mOS) was 22 months (95%CI: 20.7-NA) in methylated GBM. For the harder-to-treat unmethylated GBM patients, mPFS was 11.2 months (95%CI: 5.4-22.4) and mOS was 16 months (95%CI: 12.3-24.3). Immune profiling of peripheral blood is ongoing.

Conclusions NT-I7 is well tolerated and is associated with an increase in ALC in HGG patients after chemoradiotherapy. Phase II accrual and immune profiling are ongoing.

Acknowledgements Funding by NeoImmuneTech, Inc. and Siteman Investment Program, Siteman Cancer Center

Trial Registration Clinical Trial ID: NCT03687957

References

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2. Campian JL, Piotrowski AF, Ye X, Hakim FT, Rose J, Yan XY, Lu Y, Gress R, Grossman SA. Serial changes in lymphocyte subsets in patients with newly diagnosed high grade astrocytomas treated with standard radiation and temozolomide. J Neurooncol. 2017;135(2):343–351. doi: 10.1007/s11060-017-2580-z. Epub 2017 Jul 29. PMID: 28756593.

3. Campian JL, Ye X, Gladstone DE, Ambady P, Nirschl TR, Borrello I, Golightly M, King KE, Holdhoff M, Karp J, Drake CG, Grossman SA. Pre-radiation lymphocyte harvesting and post-radiation reinfusion in patients with newly diagnosed high grade gliomas. J Neurooncol. 2015;124(2):307–16. doi: 10.1007/s11060-015-1841-y. Epub 2015 Jun 13. PMID: 26070554; PMCID: PMC4696006.

4. Campian JL, Ghosh S, Kapoor V, Yan R, Thotala S, Jash A, Hu T, Mahadevan A, Rifai K, Page L, Lee BH, Ferrando-Martinez S, Wolfarth AA, Yang SH, Hallahan D, Chheda MG, Thotala D. Long-Acting Recombinant Human Interleukin-7, NT-I7, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models. Clin Cancer Res. 2022;28(6):1229–1239. doi: 10.1158/1078-0432.CCR-21-0947. PMID: 35031547.

Ethics Approval Each site’s respective institutional review board approved the study.

Consent Written informed consent was obtained from each participant prior to any trial related activities.